Prolamine coatings for taste masking

ABSTRACT

Prolamine fractions of grain proteins, applied as a single coating in weight ratios of 5 to 100% relative to the active substance being coated, result in the production of a liquid suspension which effectively masks the taste of orally administered drugs which often are extremely bitter. The taste masking is stable over prolonged periods of storage time of the suspension. The prolamine coating does not restrict the immediate bioavailability of the active substance. Prolamine coating is effective in masking the taste of antibiotics, vitamins, dietary fiber, analgesics, enzymes and hormones. Zein, gliadin or a mixture thereof, particularly in combination with between 2.5 and 15% of a water insoluble vegetable source oil or a wax capable of plasticizing the prolamine fraction, when applied to particles of drugs or nutritional supplements, to an effective thickness of about 1 to about 35 micrometers, are particularly effective in preventing the release of the active substance from the encapsulated particle and also in masking the unpleasant taste of the coated active substance.

This application is a Divisional of application Ser. No. 08/245,927filed May 19, 1994, allowed which is a Continuation-In-Part ofapplication Ser. No. 08/023,301 filed Feb. 26, 1993, now abandoned,which is a Continuation-in-Part of application Ser. No. 07/815,458 filedDec. 31, 1991 now abandoned.

TECHNICAL FIELD

This invention relates to oral formulations which effectively mask theunpleasant taste of drugs, such as antibiotics or benzodiazepines, ornutritionals such as dietary fiber or amino acid supplements, and othersimilar pharmaceuticals or nutritional supplements with bitter orotherwise undesirable taste characteristics. More specifically, theinvention relates to a single-coat taste-masking formulation whichencapsulates said pharmaceuticals or nutritional supplements. Moreparticularly, this invention relates to and discloses liquid suspensionsof single coated dosage forms that mask the unpleasant taste of theencapsulated agent, said suspensions retaining their taste maskingcapacity, i.e. remain stable, even though dispersed in a liquid mediumfor a significant period of time prior to use. Further, said liquidsuspensions may be swallowed without producing a bitter taste in themouth, but the encapsulated agent is immediately bioavailable uponexposure to the pH levels found in the stomach.

BACKGROUND OF THE INVENTION

Oral administration of pharmaceuticals and nutritionals is one of themost popular methods of delivery of such beneficial agents. Liquidsuspension dosage forms are a preferred route of such oraladministration for both children and adults who have difficultyswallowing capsules or tablets. Furthermore, infants cannot be giventablets or capsules. Palatability of the ingested material is anextremely important factor in ensuring the likelihood that the recipientwill ingest the pharmaceutical or nutritional. Accordingly, masking ofthe unpleasant taste characteristics of the pharmaceutical ornutritional is an important factor in the formulation of these agents.Further, the stability of the liquid suspension is an extremelyimportant factor. As used herein and in the claims the term "stability"means the ability of the liquid suspension to mask the unpleasant tasteof the encapsulated material for a significant period of time prior toingestion. In other words, use of the claimed composition results inminimal leakage of the active substance into the suspending medium.Additionally, after ingesting the pharmaceutical or nutritionalsupplement, it is often times desirable for the nutritional orpharmaceutical to be immediately available to the person in need ofsame.

Because of the strong, unpleasant taste of many pharmaceuticals ornutritional supplements, flavorings, either alone or in combination withsweeteners and other additives, have been employed to improve taste andpalatability. The formulation of a pleasant-tasting and palatableproduct through the sole use of flavorings, sweeteners and additives,however, has been unsuccessful when using beneficial agents which have aparticular bitter taste, such as the macrolide family of antibiotics, inparticular erythromycin and clarithromycin. Attempts have been made toformulate these antibiotics into suspension dosage forms or intotaste-masked chewable tablets using known coating or encapsulationprocesses with very limited success.

Japanese Kokoku Shu 45-12759, published Nov. 1, 1967, teaches that amixture of 90-99% zein and 1-20% hydroxypropylmethylcellulose (HPMC) maybe used to coat tablets for taste and odor masking. The applicationemploys the high molecular weight polymeric HPMC component (exemplifiedat levels of 10% and above) for its film-forming properties, in acoating used to prevent the disintegration of Vitamin C as measured bytemperature and time. This reference teaches that HPMC must be mixedwith zein to obtain taste masking properties.

U.S. Pat. No. 3,939,259, issued Feb. 17, 1976, employed prolamine fromcorn grain protein (i.e. zein), with approximately an equal level ofshellac and a lesser amount of ethylcellulose, to coat digitoxinparticles, but did so in an attempt to achieve a sustained releaseeffect. Since the incorporation of ethylcellulose may interfere withabsorption of the active agent in a timely manner, its incorporationinto the composition of the present invention for an immediatelyavailable agent would be unsuitable.

U.S. Pat. No. 4,384,004, issued on May 17, 1983, discloses theencapsulation of the artificial sweetener, L-aspartyl-L-phenylalaninemethyl ester, with additional coating materials, which may include zein,for increasing shelf life stability.

U.S. Pat. No. 5,098,718, issued on Mar. 24, 1992, discloses a coatingcomposition, consisting of very broad ranges of zein, a hydrophobicsubstance, an inorganic filler and an optional filler and an optionalnon-water soluble polymer, for coating feed additives which are intendedfor ruminants. The coating composition claimed in this patent is stablein the rumen and not substantially degraded in the abomasum of aruminant, but is primarily degraded by the enzymes present in the smallintestines of a ruminant. This delayed release would also be a problemwhen immediate bioavailability is desired.

U.S. Pat. No. 5,160,742, issued on Nov. 3, 1992, discloses a dualcoating composition for sustained delivery of an active substance, saidcomposition comprising at least a coating of prolamine and an entericcompound.

In comparison with these known formulations, the present inventionprovides a simple, inexpensive taste-masked stable product insuspension, while providing immediate bioavailability. This tastemasking ability, without delaying release of the beneficial agent, isrealized with a single coating layer of a simple, inexpensiveformulation consisting predominantly of a prolamine fraction of grain,with low to moderate molecular weight plasticizer needed to form thefilm coating.

SUMMARY OF THE INVENTION

The present invention is directed to an orally-administerablecomposition comprising: (a) a core mixture of a pharmaceutically activeagent or a nutritional supplement, having a surface; and (b) a singleouter polymeric coating layer comprising a prolamine fraction of grainprotein, preferably zein or giladin or mixtures thereof, and alow-to-moderate weight nonpolymeric agent for plasticizing saidprolamine, preferably a vegetable source water insoluble oil or wax,wherein by weight the ratio of prolamine to plasticizing agent is from40:1 to 4:1, preferably 20:1 to 20:3.

The present invention further relates to a composition wherein by weightthe ratio of the pharmaceutically effective agent or nutritional to theprolamine fraction is 20:1 to 1:1, and the single outer layer is from 1to about 35 micrometers thick. In particular, the invention comprises astable taste-masking liquid suspension capable of being ingested withoutproducing the unpleasant taste associated with the active agent, whilestill providing immediate bioavailability upon exposure to the pH levelsfound in the stomach of a human. The taste masking property of theclaimed composition is stable in that such compositions are able to maskthe unpleasant taste of the encapsulated active agent for a substantialperiod of time when stored as a liquid suspension, i.e., minimal leakageof the active agent from the encapsulated core occurs during storage.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of the plasma concentration versus time of both a zeincoated clarithromycin suspension and an uncoated clarithromycin tabletreference (control), administered at 125 mg of clarithromycin activityper dog. This graph illustrates the bioavailability of the claimedcomposition.

FIG. 2 is a graph of the bitterness (on a scale of 0 to 3, where 0represents no bitterness and 3 represents a strong bitterness) observedfor a clarithromycin concentration in solution.

FIG. 3 is a graph of the bitterness as a function of time after tasting,observed for the formulation of clarithromycin particles coated with asingle layer of zein and suspended in an aqueous environment for both aninitially-prepared suspension (Day 0) and a suspension which wasprepared and allowed to stand for seven days (Day 7). This comparisonillustrates the taste masking stability of the zein coated suspension.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the use of a single outer polymericcoating layer to encapsulate and thereby effectively and stably mask thetaste of pharmaceutically active agents or nutritional supplements whichhave bitter or otherwise undesirable tastes, while providing immediaterelease of the beneficial pharmaceutical or nutritional supplement uponexposure to the pH levels found in the stomach. The formulations of thepresent invention comprise: (a) a core of a pharmaceutically activeagent or nutritional supplement, as well as diluents, fillers or otherinactive ingredients necessary for the formation of the pharmaceuticalcore; and (b) a single outer polymeric coating layer comprising aprolamine fraction of cereal grain proteins and a low-to-moderatemolecular weight hydrophobic plasticizing agent for said prolamine.

Prolamines form the main protein components of cereal grains and flour.Unlike all other proteins, they can be extracted from flour with 80percent alcohol, but they are insoluble in absolute alcohol and water.The most important prolamines are zein, gliadin, and hordein. In theinstant invention, the prolamine fraction is purified from corn or wheatand includes zein or gliadin or mixtures thereof, but preferably is zein(the prolamine fraction of corn) which has been purified to between86-96% pure zein, most preferentially 92-96% purity. Additionally, theprolamines present in the preferred coating formulation will be presentin a solution consisting of 90% food grade ethanol and 10% distilledwater at a preferred level (by weight) of between 5% and 20% prolamine.

The hydrophobic plasticizing agent which is preferentially present on aweight basis between 2.5% and 25%, more preferably 5% to 15%, relativeto the prolamine fraction, is a water insoluble vegetable oil or wax,and includes, but is not limited to, fatty acids having carbon chainlengths of six to twenty-two (both saturated and unsaturated carbonchains are equally suitable), non-ionic cellulosic polymers (e.g.,hydroxypropyl cellulose and/or hydroxyethyl cellulose), andpolyvinylpyrrolidone of molecular weight range 30,000 to 400,000daltons. Most preferred hydrophobic plasticizers are fatty acids havingchain lengths six-to-eighteen carbons which are present on a weightbasis of between 5 and 15%.

Because the coating composition of the instant invention is designed torapidly degrade once the product has left the mouth, additionalingredients that lend stability to coating at a pH less than that foundin the mouth are not desired. Thus substances such as non-water solubleethers and esters of cellulose, ethylcellulose, cellulose acetate,cellulose propionate, cellulose acetate butyrate, polyvinyl esters,polyvinyl acetate, and the like, and even organic fillers, such as talcwhich is also non-water soluble, are not contemplated as ingredientswithin the scope of the present invention.

The active substances which are believed to be suitable forincorporation in the core of an encapsulated particle in accordance withthe present invention are bioactive substances including for example,analgesics, antibiotics, preferably macrolide antibiotics, oncolytics,immunogens, antidepressants and other physchotherapy drugs, antivirals,drugs to treat HIV compromised individuals and individuals with AIDS,immuno-modulators, antihistamines, decongestants, anti-inflammatoryagents, vaccines, enzymes, hormones, dietary fiber and other nutrients,antibodies and other pharmaceuticals. The foregoing list is not intendedto be inclusive but merely representative of various active compoundsboth simple and complex that are contemplated in accordance with thepresent invention. Those active agents having an especially bittertaste, such as macrolide antibiotics, specifically erythromycin andclarithromycin, are particularly suited for the present invention.

The optimum thickness of the coating material is between about 1 andabout 35 micrometers. The coating is applied as a single layer. Thepreferred level of coating consists of from about 5% to about 100% ofapplied film, where the major constituent is the prolamine fraction ofgrain protein (with the percent representing the weight of film coatingrelative to the initial weight of the encapsulated active agent). Themost preferred level of coating is between 45 to 75% by weight ofcoating to weight of the encapsulated active ingredient core.

The preparation of the formulation may be accomplished by a variety ofcoating techniques known in the art including fluidized bed coating,coacervation, or a combination thereof, and the like, as disclosed inU.S. Pat. No. 4,384,004 to Cea et al. Preferably, fluid bed coating witha rotor insert may be employed to form the initial active agent core,and fluidized bed coating with a Wurster column insert may be employedto apply the coating, as described in U.S. Pat. No. 4,800,087 to Mehtaet al. In the fluidized bed procedure, with rotor insert, for preparinga core containing the active agent as employed herein, the active agentor active agent in a matrix is charged as a powder onto a variable speedhorizontal rotor disc in an apparatus that creates an upward air currentor stream in which the particles have a rotary movement about an atleast approximately vertical axis. The particles pass through a zone offinely atomized coating material which causes the passing particles tobe coated. Additional solvents can be applied after the application ofthe coating material to better form particles of the desired size.Finally, rotor speed is increased and fluidization air volume and airtemperature are also increased to both form the coated particles andobtain the desired level of dryness. The foregoing method and apparatusare known as a fluidized bed with rotor disc and are set forth in detailin the following U.S. patent, the disclosures of which are incorporatedherein by reference: U.S. Pat. Nos. 4,323,312 and Re. 32,307.

In the fluidized bed with Wurster column procedure as applied herein forapplying a coating, the active agent cores produced with the fluidizedbed with rotor insert described above, or other means, are suspended inan apparatus that creates a strong upward air current or stream in whichthe particles move. The stream passes through a zone of finely atomizedcoating material which causes the passing particles to be coated, afterwhich the coated particles move upward through the Wurster column andthen travel downward in a fluidized condition countercurrent to a flowof heated fluidized gas whereupon they are dried. The particles mayreenter the upward stream for a further coating until the desired weightratio of coating to active core has been obtained. The foregoing methodand apparatus are known as the Wurster Process and are set forth indetail in the following U.S. patents, the disclosures of which areincorporated herein by reference: U.S. Pat. Nos. 3,089,824; 3,117,027;3,196,827; 3,241,520; and 3,253,944.

The preferred method for preparing the pharmaceutical or nutritionalcore is to comix the active agent with a portion of inactive binderconsisting of polyvinylpyrrolidone (such as Povidone™ made by theInternational Speciality Chemicals Corporation) having a molecularweight range of 30,000 to 400,000 on a weight to weight basis of 5% to65% of the active ingredient. Alternative granulating agents capable ofassisting the formation of a particle containing the active ingredientinclude hydroxypropylcellulose (such as Methocel™, Dow ChemicalCorporation), pregelatinized starch, (such as obtained from Colorcon,Inc.) or any other material suitable for use as a binding agent for theformation of particles capable of being utilized as pharmaceutically ornutritionally active core material. After dry blending, a sufficientportion of water or food grade alcohol is added to the dry blend toyield a wet granulation mixture. This material may be either oven-driedunder mild heat or dried in a fluidized bed air-drying system, which iscapable of performing the task of drying in a more efficient, less timeconsuming fashion. The particles are then dried to a specific level ofdryness (based on weight loss measurements) and milled to produce asmall particle size range. These particles may then be sieved to collectthe fraction of particles of a particular size range for subsequentcoating. Alternate methods for preparing particles are equally useful atcreating particles of a suitable size range.

Following production of the particles of the active agent havingsuitable size, these particles are then coated or encapsulated with theprolamine coating material. The prolamine coating materials are preparedas a solution capable of being uniformly atomized. The solubility ofzein requires a solvent containing both polar and non-polar groups inthe proper ratio. The proper ratio of polar and non-polar groups can beobtained with single solvents or two or more solvent mixtures. Examplesof suitable single solvents are acetic acid, lactic acid, propionicacid, and propylene glycol. The aqueous alcohols are preferred assolvents in many applications. Examples of suitable alcohol/watersystems are methanol/water, ethanol/water, isopropanol/water, andn-butanol/water. To obtain complete solubility above the cloud point,the ratio of alcohol to water varies for each alcohol chosen and mixedsolvent final temperature. If desired, other ingredients such asplasticizers or hydrophobic substances may be added to improve theproperties of the final coating. Suitable plasticizers includetriethylene glycol, propylene glycol, oleic acid, lactic acid acetamide,ethylene glycol monooleate, glycerin, glyceryl monostearate, dibutyltartrate, and tricresyl phosphate. Suitable hydrophobic substancesinclude vegetable and animal fats, either unhydrogenated, hydrogenated,or partially hydrogenated, fatty acids, with representative materialscomprising palm oil, palm kernel oil, soybean oil, rapeseed oil, ricebran oil, sunflower oil, safflower oil, coconut oil, castor oil, MCToil, also known as glycerine ester of C6-C20 fatty acids derived fromcoconut oil, and mixtures thereof. Other hydrophobic substances alsouseful herein may be selected from monoglycerides, distilled mono- anddiglycerides, triglycerides, acetylated mono-and diglycerides,triglycerides and mixtures thereof. The plasticizer may be added inknown effective amounts within the scope of the invention. In general,amounts of about 5% to about 25% by weight of zein are suitable. Thethickness of the single layer coating is easily varied by adjusting thesolids concentrations of the prolamine and hydrophobic plasticizerdissolved in the coating solution.

The formulation of the present invention may be incorporated into avariety of pharmaceutical and nutritional products, includingpharmaceutical suspensions, pediatric infant formulas, and liquidnutritional supplements.

As used herein and in the claims when a coating component is stated asbeing as a percent of a particle, it should be understood that thecoating component by itself is expressed as a weight percent of theparticle. In the examples, all values of the weight percent of coatingcomponents were determined by analytical analysis. In addition to thestated weight percent of the coating component contained in the coat,the coating would also contain any specified plasticizer or hydrophobicsubstance at the weight percent specified in the example.

Example 1

A. Preparation of Clarithromycin: Polyvinylpyrrolidone Particles,

To a pharmaceutically active core consisting of 90% clarithromycin and10% polyvinylpyrrolidone (Povidone, K-30, ISP Corp), a sufficient amountof food grade ethanol was added with mixing to form a wet mass. The wetgranulation was then dried in an oven set at between 50° and 60° C.until the loss of drying (hereinafter referred to as LOD) was less than1%. These particles were then ground to a smaller size and fractionatedusing a sieve having a 40-80 mesh. The fraction of particles having asize between 177 and 420 micron was collected.

B. Preparation of Zein-coated Clarithromycin: PolyvinylpyrrolidoneParticles.

To 4 kg of clarithromycin: polyvinylpyrrolidone particles, prepared asdescribed above, was applied 2.8 kg of solids contained in a coatingformulation consisting of zein (93%) and medium chain triglycerides(7%). This coating formula was dispersed in a mixture of 90% food gradeethanol and 10% distilled water to a level of 10.75% solids (prolaminefraction and medium chain triglycerides), in this cosolvent mixture. Thecoating was performed in a Glatt GPCG-5 bottom spray particle coaterwith a fluidized bed and a Wurster column. Inlet temperature wasmaintained between 39° and 45° C., with the exhaust temperature between26° and 29° C., and the atomization pressure on the spray nozzle wasmaintained between a range of 26 and 30 pounds per square inch. The flowrate of application of the coating liquid to the particles wasmaintained in the range of 10 to 15 mL per minute. The thickness of thesingle layer coating is easily varied by adjusting the solidsconcentrations of the prolamine and hydrophobic plasticizer dissolved inthe coating solution.

Example 2 Dissolution of Zein-coated Clarithromycin:Polyvinylpyrrolidone Particles as a Function of pH.

The zein coated clarithromycin: polyvinylpyrrolidone particles, preparedas described in Example 1, were tested using a dissolution apparatus toevaluate the percent of active ingredient released into a 900 mLdissolution bath of pH buffered solution over a two hour period. A doseof 125 mg of clarithromycin activity was used as a representative doseand dissolution was tested at pH 2.0, 5.0 and 6.8. Samples werewithdrawn at 30, 60, 90 and 120 minutes. The results, as shown by Table1, indicate no active agent was released at pH 6.8. Rapid release of theactive agent was observed at pH 2.0.

                  TABLE 1                                                         ______________________________________                                        Dissolution of Zein-coated Clarithromycin: Polyvinyl-                         pyrrolidone Particles as a Function of solution pH.sup.1.                                Percent (%) Clarithromycin Released                                Time (minutes)                                                                             pH 2       pH 5       pH 6.8                                     ______________________________________                                        30           80.8(8.1).sup.2                                                                          35.9(22.3) nd.sup.3                                   60           90.9(3.0)  52.9(13.2) nd                                         90           94.7(4.1)  62.4(8.5)  nd                                         120          96.3(2.8)  69.4(11.7) nd                                         ______________________________________                                         .sup.1 Particles coated with 70% weight coating to weight of particle.        .sup.2 Average (± standard deviation); number of determinations in eac     case = 3.                                                                     .sup.3 No detectable release.                                            

Example 3 Release of Zein-coated Clarithromycin: PolyvinylpyrrolidoneParticles as a Function of Storage Time

To a solution in which sodium bicarbonate (50 mg/5 mL) was dissolved,125 mg/5 mL of zein coated clarithromycin activity (accounting forpotency of the active agent and the particles), was added, shaken andobserved for release of active agent as a function of time. The final pHof this suspension was greater than pH 6.0. Samples were withdrawn,filtered, and measured at 0, 4, 24, 72, and 196 hours. The samples werefiltered to remove the suspended particles and the clear flitrate wasanalyzed for clarithromycin content. The results, as shown in Table 2,below, indicate that very low levels of active drug are released fromthe zein encapsulated material over prolonged periods of storage time.Even after more than 8-days storage, less than 0.5% of the encapsulatedclarithromycin had leaked through the zein coating.

                  TABLE 2                                                         ______________________________________                                        Release of Zein-coated Clarithromycin: Polyvinyl-                             pyrrolidone Particles as a Function of Storage Time.                                     Concentration                                                      Time (hours)                                                                             (micrograms/mL)                                                                            Percent (%) Release                                   ______________________________________                                         0         20           0.08                                                   4         60           0.24                                                  24         99           0.40                                                  72         118          0.47                                                  196        102          0.41                                                  ______________________________________                                    

Thus, this example shows that a suspension, having a final pH greaterthan about pH 6.0, containing particles having an active substance in acore coated with a single layer of a mixture consisting of prolamine andhydrophobic plasticizer has been reduced to practice, with minimalleakage of the active substance into the suspending medium.

Example 4 Formulation of Zein Coated Clarithromycin.

Zein coated clarithromycin, comprising 70% coating was formulated asfollows:

    ______________________________________                                        Ingredient    Amount per dose (5 mL)                                          ______________________________________                                        Coated clarithromycin                                                                       260      mg (125 mg activity)                                   Sucrose       3000     mg                                                     Xanthan Gum   7.5      mg                                                     Silica Gel    10.0     mg                                                     Potassium Sorbate                                                                           20.0     mg                                                     Bubble Gum Flavor                                                                           14.0     mg                                                     Sodium Bicarbonate                                                                          50.0     mg                                                     Totals:       3361.5   mg per 5 mL final volume.                              ______________________________________                                    

The purpose of this example is to demonstrate that the particles inaccordance with the invention may be dispersed in a liquid medium toyield a taste masking suspension of the active substance. As used hereinand in the claims, a "liquid suspension" is understood to be an oilbased liquid, aqueous based liquid, or a liquid that has a base which isa combination of water and oil. As used herein and in the claims, a"liquid" is understood to mean a state of matter in which the moleculesare relatively free to change their positions with respect to each otherbut are restricted by cohesive forces to maintain a relatively fixedvolume.

Example 5 Bioavailability of Zein-coated Clarithromycin

The bioavailability of zein-coated clarithromycin, formulated asdescribed in Example 4, was conducted in a beagle dog model using asingle cross-over design. The study compared single dose immediaterelease containing 125 mg of clarithromycin activity to the zeinencapsulated clarithromycin particles prepared as described in Example1, and formulated as described in Example 4. The release ofclarithromycin was demonstrated by a cross over comparison of thebioavailability of the formula in a beagle dog model compared to atablet reference containing the same amount of clarithromycin. The crossover design allowed the same dogs to receive both the zein coatedclarithromycin suspension as well as the clarithromycin reference tabletcontaining the same amount of clarithromycin (125 mg of clarithromycinactivity). The results, illustrated in FIG. 1, demonstrate that thezein-coated clarithromycin suspension did not release the clarithromycinin suspension (as shown by a representative suspension in Example 3,Table 2), but rapidly released the active drug in the low pH conditionsof the gastrointestinal tract of the dog. As illustrated in FIG. 1 thelevel of clarithromycin in the plasma of the dogs, indicated thatequivalent adsorption of the zein- encapsulated clarithromycin and ofclarithromycin contained in the uncoated rapid release tablet occurred.

Example 6 Flavor Evaluation of Zein-coated Clarithromycin

The concept that the taste masking of the unpleasant taste of an activesubstance suspended in a liquid is primarily achieved by the exteriorcoating of the active substance is supported by studies performed on themacrolide antibiotic, clarithromycin.

Comparative flavor evaluation, noting characteristics of bitterness ofthe zein coated clarithromycin particles suspended in solution wasconducted. The formulation used was that described in Example 4, and wascompared with uncoated clarithromycin in solution as a standardreference for the level of bitterness observed for the various samples.The study was conducted using a panel of specially trained flavor andtaste specialists. This taste panel standardized their palate with theuse of reference samples which were, in this case, solutions containingvarying amounts of uncoated clarithromycin, herein after also referredto as "standards". The study consists of swirling a dose of the solutionor suspended formulation in the mouth and then ranking bitterness,relative to the standards, as a function of time after tasting it. Theperiod of time after tasting is evaluated in the event that particlesremain or get lodged in the oral cavity before being removed by salivarysecretions.

The bitterness dose response for the uncoated clarithromycin in solutioncan be seen in FIG. 2 and the corresponding level of response for thezein coated clarithromycin suspension is shown in FIG. 3, as a functionof time after tasting. FIG. 2 illustrates that a solution containing 3parts per million (ppm) of uncoated clarithromycin yields a bitternessindex of 0.2, whereas a solution containing 10 ppm of uncoatedclarithromycin has bitterness index of about 1.1, and a solutioncontaining 20 ppm has a bitterness value of 2.5, etc. FIG. 3 shows thatimmediately after production (Day 0), the zein coated clarithromycinsuspension exhibits a bitterness index below 1.0 corresponding to a freeuncoated clarithromycin concentration of less than 10 ppm. FIG. 3further illustrates that even after seven days storage (Day 7), the zeincoated clarithromycin suspension exhibits a bitterness index below 1.5.This value corresponds to about 15 ppm of uncoated clarithromycin asshown in FIG. 2. Thus, FIG. 3 shows even after seven days of storage ofthe zein coated clarithromycin suspension, that the levels of freeclarithromycin available for interaction with the taste buds is below 15ppm. This demonstrates the ability of the zein coating to effectivelymask the taste of a very bitter pharmaceutically active agent such asclarithromycin. FIG. 3 also demonstrates the ability of the zein coatingto produce a stable formulation which releases not more than 15 ppm ofclarithromycin after seven days of storage of the zein coatedclarithromycin suspension.

By way of further explanation, it should be noted that the testedpreparation contained 125 mg of clarithromycin per 5 ml of suspension(see Example 4). This corresponds to well over 185,000 ppm ofclarithromycin. Thus FIG. 3 illustrates that substantially less than0.01% of the available clarithromycin is released from the zein coatedclarithromycin-polyvinylpyrrolidone particles of Example 4 even afterseven days storage.

Example 7- Comparative

A. Preparation of Clarithromycin Pellets.

To a pharmaceutically active core consisting of 100% clarithromycin, asufficient amount of food grade ethanol was added with mixing to form awet mass. The wet granulation was then dried in an oven set between 50°and 60° C. until the loss of drying (LOD) was less than 1%. Theseparticles were then grounded to a smaller size, sieved through a 40-80mesh and the fraction of particles in the size range between 177 and 420microns was collected.

B. Preparation of Zein/Stearic Acid/Talc-Coated Clarithromycin

A zein based coating formula was prepared to coat the clarithromycinparticles produced above. The coating solution was made by first adding1890 grams of 200 proof grade ethanol to 810 grams of distilled water.As this solution was being mixed, 165 grams of zein, 120 grams ofstearic acid, and 15 grams of talc were slowly added in succession. Theresultant solution was mixed until the solids were in solution. Afterthe solids were in solution, the clarithromycin particles, prepared asdescribed above, were coated. The coating was performed in a GlattGPCG-5 bottom spray particle coater with a fluidized bed and a Wurstercolumn. Inlet temperature was maintained between 39° and 45° C., withthe exhaust temperature between 26° and 29° C., and the atomizationpressure on the spray nozzle was maintained between a range of 26 to 30pounds per square inch. The flow rate of application of coating liquidto the particles was maintained in the range of 10 to 15 mL per minute.The clarithromycin particles were coated with various amounts of theabove coating. Specifically, the particles had coating of 20, 40 and 60percent (w/w) based on the weight of the clarithromycin particles. Thethickness of the single layer coating is easily varied by adjusting thesolids concentrations of the prolamine and hydrophobic plasticizerdissolved in the coating solution.

C. Dissolution of Zein Coated Clarithromycin as a Function of Time in pH2 Buffer.

The zein coated clarithromycin particles, prepared as described above,were tested using a dissolution apparatus to evaluate the percent ofactive ingredient released into a 900 mL dissolution bath of pH-bufferedsolution at a temperature of 40° C. A dose of 125 mg of clarithromycinactivity was used as a representative dose and dissolution was tested atpH 2.0 and 6.0. samples were withdrawn at 60, 120, 240, and 360 minutes.The results, as shown by Tables 3, 4, and 5 below, indicate rapidrelease of active drug for all coating concentrations at pH 2.0.Increasingly, proportionally to the coating amount, slow release of theactive drug was observed at pH 6.0.

                  TABLE 3                                                         ______________________________________                                        Level of Coating: 20%                                                                    Percent of Clarithromycin Released                                 Time (minutes)                                                                             pH 2.0       pH 6.0                                              ______________________________________                                         60           97          38                                                  120          100          55                                                  240          100          75                                                  360          100          85                                                  ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        Level of Coating: 40%                                                                    Percent of Clarithromycin Released                                 Time (minutes)                                                                             pH 2.0       pH 6.0                                              ______________________________________                                         60           98          21                                                  120          100          30                                                  240          100          42                                                  360          100          57                                                  ______________________________________                                    

                  TABLE 5                                                         ______________________________________                                        Level of Coating: 60%                                                                    Percent of Clarithromycin Released                                 Time (minutes)                                                                             pH 2.0       pH 6.0                                              ______________________________________                                         60          100          11                                                  120          100          16                                                  240          100          24                                                  360          100          31                                                  ______________________________________                                    

As shown in Table 1, for a 70% coating, no detectable release of activesubstance occurred at pH 6.8. This example shows that a suspensioncontaining particles having an active substance in a core coated with asingle layer of a mixture consisting of prolamine and hydrophobicplasticizer and exhibiting minimal leakage of the active substance intothe suspension medium has been reduced to practice.

Although the invention has been exemplified in specific modifications,the details are not to be construed as limitations, for it will beapparent that various equivalent, changes and modifications may beemployed without departing from the spirit and scope thereof, it beingunderstood that such equivalent embodiments are intended to be includedtherein.

What is claimed is:
 1. A method for preparing a suspension of anencapsulated active substance, said suspension having thecharacteristics of stable taste masking and immediate release of theactive substance in the gastrointestinal tract, said method consistingessentially of the steps of:(a) forming particles of an active substanceselected from the group consisting of clarithromycin and erythromycin bydissolving said substance in a solvent, drying and sieving the resultantpowder to yield particles having a size in the range of between about175 microns and about 420 microns; (b) encapsulating the particles witha single outer coat by contacting the particles with a coating solutioncomprising a mixture of a prolamine and a hydrophobic plasticizerselected from water-insoluble vegetable source oils and waxes whereinsaid oils and waxes have a fatty acid chain length of about 6 to about22carbon atoms; (c) collecting the coated particles; and (d) suspendingthe coated particles in a solution having a final pH greater than about6.5.
 2. The method according to claim 1 wherein said prolamine comprisesan amount of from about 30% to about 70% by weight of the sum of theweights of said active agent and said single coating layer, and whereinthe ratio of prolamine to said plasticizers and hydrophobic substancesin said coating layer is from 40:1 to 4:1.
 3. The method according toclaim 2 wherein said prolamine comprises an amount of from about 40% toabout 60% by weight of the sum of the weights of said active agent andsaid single coating layer.
 4. The method according to claim 2, whereinsaid ratio of prolamine to hydrophobic plasticizers is from 20:1 to20:3.
 5. The method according to claim 1, wherein the weight ratio ofsaid active substance to said coating layer is from 20:1 to 1:1 and thecoating is from about 1 to about 35 micrometers thick.
 6. The methodaccording to any one of claims 1 through 4 and 5 wherein the prolamineis selected from the group consisting of zein, giladin and hordein. 7.The method according to any one of claims 1 through 4 and 5 wherein theprolamine is zein.
 8. A method for preparing a suspension of anencapsulated active substance, said suspension having thecharacteristics of stable taste masking and immediate release of theactive substance in the gastrointestinal tract; said method consistingessentially of the steps of:(a) forming particles of an active substanceby dissolving said substance in a solvent, drying and sieving theresultant powder to yield particles having a size in the range ofbetween about 175 microns and about 420 microns. (b) encapsulating theparticles with a single outer coat by contacting the particles with acoating solution comprising a mixture of a prolamine and a hydrophobicplasticizer selected from the group consisting of triethylene glycol,propylene glycol, oleic acid, lactic acid, acetamide, ethylene glycolmonooleate, glycerin, glyceryl monostearate, dibutyl tartrate, tricresylphosphate, vegetable oils, animals fats, monoglycerides, diglycerides,triglycerides, acetylated monoglycerides, acetylated diglycerides, andmixtures thereof; (c) collecting the coated particles; and (d)suspending the coated particles in a solution having a final pH greaterthan about 6.5.
 9. The method according to claim 8 wherein saidprolamine comprises an amount of from about 30% to about 70% by weightof the sum of the weights of said active agent and said single coatinglayer, and wherein the ratio of prolamine to said plasticizers andhydrophobic substances in said coating layer is from 40:1 to 4:1. 10.The method according to claim 9 wherein said prolamine comprises anamount of from about 40% to about 60% by weight of the sum of theweights of said active agent and said single coating layer.
 11. Themethod according to claim 8 wherein said ratio of prolamine tohydrophobic plasticizers is from 20:1 to 20:3.
 12. The method accordingto claim 8 wherein the weight ratio of said active substance to saidcoating layer is from 20:1 to 1:1 and the coating is from about 1 toabout 35 micrometers thick.
 13. The method according to claim 8 whereinsaid active substance is a nutritional supplement selected from thegroup consisting of proteins, amino acids, vitamins and dietary fiber.14. The method according to claim 8 wherein the prolamine is selectedfrom the group consisting of zein, gliadin and hordein.
 15. The methodaccording to claim 8 wherein the prolamine is zein.
 16. The methodaccording to claim 8 wherein said hydrophobic plasticizer is a vegetableoil selected from the group consisting of palm oil, palm kernel oil,soybean oil, rapeseed oil, rice bran oil, sunflower oil, safflower oil,coconut oil, castor oil and MCT oil.
 17. The method according to claim 8wherein the active substance is selected from the group consisting ofanalgesics, antibiotics, anti-depressants, antivirals, antibodies,immunomodulators, oncolytics, immunogens, hormones, vaccines, enzymesand nutritional supplements.
 18. The method according to claim 8 whereinsaid active substance is an antibiotic selected from the groupconsisting of clarithromycin and erythromycin.